Dipiperazine calcium citrate and method of preparing same



United States Patent 9 ice fffiiii tural configuration of thisarrangement may be postulated as follows:

2,708,195 f DIPTPERAZINE CALCIUM CITRATE AND NIETHOD GF PREPARING SAME/C\ /C\ Bernard Abramson, White Plains, and Ernest L. Beais, &Tuckaho-e, N. Y., assignors to Burroughs Wellcome & C0. (U. S. A.) Inc.,Tuckahoe, N. Y., a corporation of Ca New York CH2 0 o o 0 on;

10 No Drawing. Application March 10, 1954, i N HZ Serial No. 415,413 0 O4Cl2im (C -26026 The difference in taste as compared with tripiperazinedicitrate could be a matter of solubility, but whatever the reason thesalt which is the subject of the present invention has all the desirableproperties for a medicinal preparation in dry form for tablation.

The novel compound may be formed by combining the proper molecularproportion of citric acid with calcium carbonate and thereafter addingto the solution the required moles of piperazine hexahydrate.

Our invention relates to novel compositions suitable for oraladministration in the treatment of pin worm infections. Pin worms areparasitical organisms Whose eggs are normally introduced into the systemorally by contact with contaminated objects. In the digestive tract theeggs hatch and the worms eventually reach the colon or large intestineand occasionally the appendix. The Example adult forms of the parasitemature in these regions atv Two moles of anhydrous citric acid aredissolved in taining a length of about one-half inch. The gravid 1250cc. of distilled water while the temperature of the females then issuefrom the anus usually at night and solution is maintained below C. Tothis is slowly deposit their eggs. These activities frequently causeiradded one mole of calcium carbonate while the mixture ritation,itching and distress in the affected areas. is stirred. When theetfervescence ceases and a clear Suggestions for the use of the chemicalpiperazine, solution develops two moles of piperazine hexahydrateusually as the hydrate, have been made for treatment 30 are added to thesolution while the temperature is mainof pin worm infections and themedication is administained below 30 C. The solution is then filteredimtered as a neutralized solution. Unsuccessful attempts mediately and1250 cc. of anhydrous alcohol slowly have been made at the formulationof the drug in tablet added to the filtrate with rapid stin'ing. Thestirring is form and most dry preparations are either unstable orcontinued until a thick, White, crystalline slurry forms have anextremely unpleasant or bitter taste. in the solution. The solids arefiltered and Washed with Many piperazine salts are hydroscopic or cannotbe 625 cc. of alcohol and then with an additional 625 obtained in theform of discrete compounds of fixed and cc. of anhydrous alcohol. Theresulting dipiperazine caldefinite composition. Still others, such aspiperazine dicium dicitrate is dried at a temperature of 120 F. andhydrochloride, have an objectionably strong acid taste, compressed intotablet form. while many are disagreeably saline to the tongue. 40 Thecompound was a white amorphous powder, non- In the attempt to provide anacceptable salt of piperhydroscopic, stable to heat and entirelyodorless. It was azine evaporation of an aqueous solution of piperazineslightly soluble in water, soluble in dilute HCl, insoluble citratecontaining mole for mole of acid and base proin alcohol, acetone andether. It had a molecular weight duces a salt of unobjectionable flavor,but on drying of approximately 594.59. By analysis the piperazine,

becomes deficient in piperazine. Another salt formunitrogen and calciumcontents corresponded to the theolated by combining 3 moles ofpiperazine with 2 moles 4D retical quantities. of citric acid issurprisingly stable on drying but in taste W Claim: is acidulous andsaline. 1. Dipiperazine calcium dicitrate.

It has been found that a calcium piperazine citrate 2. The method offorming diPiPeTaZine Calcium dicitrate which comprises reacting twomoles of citric acid with one mole of calcium carbonate and two moles ofcontaining one atomic proportion of calcium to two molecular proportionseach of piperazine and citric acid produces a dry, compressiblepiperazine salt that is pra piperazine hexahydrate and recovering theproduct. tically tasteless and remarkably stable in composition. Th m he fOI'th in l im 2 wher in he tem- This compound is dipiperazine calciumdicitrate. In the perature of the reaction is maintained below 30 C.light of the related piperazine citrates and the known The method Setforth in claim 2 wherein h r tendency of i i id to f poorly dissociatedtion mixture is treated first with aqueous alcohol and plex salts itappears likely that some sort of sterically enthen Wlth anhydrousalcoholclosed complex results from the reaction. The struc- Noreferences cited.

1. DIPIPERAZINE CALCIUM DICTRATE.
 2. THE METHOD OF FORMING DIPIPERAZINECALCIUM DICITRATE WHICH COMPRISES REACTING TWO MOLES OF CITRIC ACID WITHONE MOLE OF CALCIUM CARBONATE AND TWO MOLES OF PIPERZAINE HEXAHYDRATEAND RECOVERING THE PRODUCT.